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The role of PPARγ as a thrifty gene both in mice and humans

Published online by Cambridge University Press:  09 March 2007

Kazuo Hara ,
Naoto Kubota ,
Kazuyuki Tobe ,
Yasuo Terauchi ,
Hiroshi Miki ,
Kajuro Komeda ,
Hiroyuki Tamemoto ,
Toshimasa Yamauchi ,
Ryoko Hagura  and
Chikako Ito
...Show all authors
Kazuo Hara
Affiliation:
Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655 The Institute for Diabetes Care and Research, Asahi Life Foundation, Tokyo 100-0005
Naoto Kubota
Affiliation:
Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655
Kazuyuki Tobe
Affiliation:
Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655
Yasuo Terauchi
Affiliation:
Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655
Hiroshi Miki
Affiliation:
Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655
Kajuro Komeda
Affiliation:
Division of Laboratory Animal Science, Animal Research Center, Tokyo Medical University, Tokyo 160-8402
Hiroyuki Tamemoto
Affiliation:
Department of Molecular Medicine, Institute for Molecular and Cellular Regulation, Gunma University, Gunma 371-8512
Toshimasa Yamauchi
Affiliation:
Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655
Ryoko Hagura
Affiliation:
The Institute for Diabetes Care and Research, Asahi Life Foundation, Tokyo 100-0005
Chikako Ito
Affiliation:
Hiroshima Atomic Bomb Casualty Council Health Management Center, Hiroshima 730–0052, Japan
Yauso Akanuma
Affiliation:
The Institute for Diabetes Care and Research, Asahi Life Foundation, Tokyo 100-0005
Takashi Kadowaki*
Affiliation:
Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655
*
*Corresponding author: Takashi Kadowaki, M.D., Ph.D. Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan, tel +81 3 3815 5411 ext. 33111, fax +81 3 5689 7209, email [email protected]
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Abstract

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The biological role of peroxisome proliferator-activated receptor γ (PPARγ) was investigated by gene targeting and case±control study of the Pro12Ala PPARγ2 polymorphism. Homozygous PPARγ-deficient embryos died at 10.5–11.5 days post conception (dpc) due to placental dysfunction. Heterozygous PPARγ-deficient mice were protected from the development of insulin resistance due to adipocyte hypertrophy under a high-fat diet, whose phenotypes were abrogated by PPARγ agonist treatment. Heterozygous PPARγ-deficient mice showed over-expression and hypersecretion of leptin despite the smaller size of adipocytes and decreased fat mass, which may explain these phenotypes at least in part. This study reveals a hitherto unpredicted role for PPARγ in high-fat diet-induced obesity due to adipocyte hypertrophy and insulin resistance, which requires both alleles of PPARγ. A Pro12Ala polymorphism has been detected in the human PPARγ2 gene. Since this amino acid substitution may cause a reduction in the transcriptional activity of PPARγ, this polymorphism may be associated with decreased insulin resistance and decreased risk of type 2 diabetes. To investigate this hypothesis, we performed a case±control study of the Pro12Ala PPARγ2 polymorphism. In an obese group, subjects with Ala12 were more insulin sensitive than those without. The frequency of Ala12 was significantly lower in the diabetic group, suggesting that this polymorphism protects against type 2 diabetes. These results revealed that in both mice and humans, PPARg is a thrifty gene mediating type 2 diabetes.

Keywords

ObesityThiazolidinediones
Type
Research Article
Information
British Journal of Nutrition , Volume 84 , Issue S2 , December 2000 , pp. S235 - S239
Copyright
Copyright © The Nutrition Society 2000

References

Boden, G (1997) Role of fatty acids in the pathogenesis of insulin resistance and NIDDM. Diabetes 46, 3–10.CrossRefGoogle ScholarPubMed
Deeb, SS, Fajas, L, Nemoto, M, Pihlajamaki, J, Mykkanen, L, Kuusisto, J, Laakso, M, Fujimoto, W & Auwerx, J (1998) A Pro12Ala substitution in PPARγ2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity. Nature Genetics 20, 284–287.CrossRefGoogle ScholarPubMed
Frederich, RC, Hamann, A, Anderson, S, Lollmann, B, Lowell, BB & Flier, JS (1995) Leptin levels reflect body lipid content in mice: evidence for diet-induced resistance to leptin action. Nature Medicine 1, 1311–1314.CrossRefGoogle ScholarPubMed
Friedman, JM & Halaas, JL (1998) Leptin and the regulation of body weight in mammals. Nature 395, 763–770.CrossRefGoogle ScholarPubMed
Hara, K, Okada, T, Tobe, K, Yasuda, K, Mori, Y, Kadowaki, H, Hagura, R, Akanuma, Y, Kimura, S, Ito, C & Kadowaki, T (2000) The Pro12Ala polymorphism in PPARγ2 may confer resistance to type 2 diabetes. Biochemical and Biophysical Research Communications 271, 212–216.CrossRefGoogle ScholarPubMed
Hotamisligil, GS, Shargill, NS & Spiegelman, BM (1993) Adipose expression of tumor necrosis factor α: direct role in obesitylinked insulin resistance. Science 259, 87–91.CrossRefGoogle ScholarPubMed
Kubota, N, Terauchi, Y, Miki, H, Tamemoto, H, Yamauchi, T, Komeda, K, Satoh, S, Nakano, R, Ishii, C, Sugiyama, T, Eto, K, Tsubamoto, Y, Okuno, A, Murakami, K, Sekihara, H, Hasegawa, G, Naito, M, Toyoshima, Y, Tanaka, S, Shiota, K, Kitamura, T, Fujita, T, Ezaki, O, Aizawa, S & Kadowaki, T (1999) PPARγ mediates high-fat diet-induced adipocyte hypertrophy and insulin resistance. Molecular Cell 4, 597–609.CrossRefGoogle ScholarPubMed
Lehmann, JM, Moore, LB, Smith-Oliver, TA, Wilkison, WO, Willson, TM & Kliewer, SA (1995) An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor g. Journal of Biological Chemistry 270, 12953–12956.CrossRefGoogle Scholar
Matthews, DR, Rudenski, AS, Naylor, BA, Treacher, DF & Turner, RC (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28, 412–419.CrossRefGoogle ScholarPubMed
Okuno, A, Tamemoto, H, Tobe, K, Ueki, K, Mori, Y, Iwamoto, K, Umesono, K, Akanuma, Y, Fujiwara, T, Horikoshi, H, Yazaki, Y & Kadowaki, T (1998) Troglitazone increases the number of small adipocytes without the change of white adipose tissue mass in obese Zucker rats. Journal of Clinical Investigation 101, 1354–1361.CrossRefGoogle ScholarPubMed
Saltiel, AR & Olefsky, JM (1996) Thiazolidinediones in the treatment of insulin resistance and type II diabetes. Diabetes 54, 1661–1669.CrossRefGoogle Scholar
Spiegelman, BM & Flier, JS (1998) Adipogenesis and obesity: rounding out the big picture. Cell 87, 377–389.CrossRefGoogle Scholar
Spiegelman, BM (1998) PPARγ adipogenic regulator and thiazolidinedione receptor. Diabetes 47, 507–514.CrossRefGoogle ScholarPubMed
Yen, CJ, Beamer, BA, Negri, C, Silver, K, Brown, KA, Yarnall, DP, Burns, DK, Roth, J & Shuldiner, AR (1997) Molecular scanning of the human peroxisome proliferator activated receptor γ (hPPARγ) gene in diabetic Caucasians: identification of a Pro12Ala PPARγ2 missense mutation. Biochemical and Biophysical Research Communications 241, 270–274.CrossRefGoogle Scholar